International Immunopharmacology 77 (2019) 105967
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Potential use of edaravone to reduce speciﬁc side eﬀects of chemo-, radioand immuno-therapy of cancers
Christian Bailly OncoWitan, Lille (Wasquehal) 59290, France
A R T I C LE I N FO
A B S T R A C T
Keywords: Edaravone Cancer Chemotherapy Radiotherapy Immunotherapy Inﬂammation ALS Oxygen radicals
The drug edaravone (EDA) is prescribed for the treatment of patients with amyotrophic lateral sclerosis or after an acute cerebral infarction. This synthetic pyrazolone derivative is a potent scavenger of oxygen free radicals and also functions as a modulator of transcription factors, repressing NFκB and activating Nrf2, to regulate oxidative stress. EDA displays complementary anti-oxidative and anti-inﬂammatory eﬀects. The injectable small molecule is currently investigated for the treatment of several non-neurological diseases. The potential interest of EDA in oncology is reviewed here. EDA is a mild antiproliferative agent but has been found to enhance signiﬁcantly the anticancer and antimetastatic activities of irinotecan in a colon cancer model. Anticancer derivatives of EDA have been designed but they generally display a limited antiproliferative activity. The antioxidant and anti-inﬂammatory activity of EDA can be best exploited to protect non-tumor cells from damages induced by chemotherapeutic drugs and radiations. Notably EDA can reduce the renal dysfunction induced by cisplatin, the neurotoxicity of cyclophosphamide and the cardiotoxicity of doxorubicin. Upon treatment with EDA, a signiﬁcant improvement in neurologic symptoms has been observed in patients with nasopharyngeal carcinoma after radiotherapy. The drug could be used to limit radiation-induced brain injury or oral mucositis. EDA was found to ameliorate autoimmune thyroiditis (Hashimoto thyroiditis), which is a frequent side eﬀect observed after treatment of cancer patients with monoclonal antibodies targeting the immune checkpoint PD-1. Therefore, EDA could also be useful to reduce speciﬁc side eﬀects of immuno-therapy. Collectively, the information suggests that the medical use of EDA, a drug with a proven safety after 18 years of use in brain-related Human diseases, could be extended to cancer-related conditions.
Chemical compounds studied in this article: Cisplatin (PubChem CID: 441203) Edaravone (PubChem CID: 89-25-8) Irinotecan (PubChem CID: 97682-44-5) Masitinib (PubChem CID: 790299-79-5) Riluzole (PubChem CID: 1744-22-5)
1. Introduction Edaravone (EDA) is a potent antioxidant used since 2001 in Japan for the management of cerebral infarction (stroke). Later the drug was approved worldwide for the treatment of adult patients with amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s disease), a progressive neurodegenerative disorder of motor neurons accompanied with muscle atrophy. It was initially approved in Japan and South Korea in 2015 and then in diﬀerent countries; it has received approval from US-FDA in May 2017 and Chinese-NMPA in August 2019 for the treatment of ALS [1,2]. Chemically, EDA is a phenyl-pyrazolone derivative showing a high reactivity with oxidative free radicals, through electron transfer from edaravone anion (Fig. 1). Administered iv – there is no oral dosage formulation of EDA - the drug can easily cross the blood-brain barrier (BBB) and is weakly subjected to eﬄux by the P-gp. EDA displays a high brain penetration capacity and lipophilic
formulation of EDA can further enhance the uptake into the brain . EDA mainly reacts with oxygen radicals by oxidation into 4-oxoedaravone and then OPB (2-oxo-3-(phenylhydrazono)butanoic acid), the peroxidation product. It reacts also with peroxynitrite as well as lipid peroxyl radicals. EDA exhibits a keto-enol tautomerism, with three isomeric structures: the keto, enol and amine forms and the anion form also possesses three resonance structures (Fig. 1) . The potent radical-scavenging and antioxidant activities of EDA account for its clinical eﬃcacy. The drug is primarily used as a neurovascular protective agent for the management of cerebral infarction and ALS but other clinical indications have been discussed such as the management of glaucoma to lower intraocular pressure  or to limit the progression of cardiac dysfunction in heart failure [6,7]. In fact, the use of the drug to treat various non-neurological diseases and conditions has been proposed: to treat retinal, myocardial, lung, intestinal, liver, pancreatic, renal, bladder and testicular injuries, but also sepsis and burns .
Abbreviations: ALS, amyotrophic lateral sclerosis; BBB, blood-brain barrier; EDA, edaravone; IL, interleukin; NSC, neural stem cells; ROS, reactive oxygen species E-mail address: [email protected]
, http://www.oncowitan.com. URL: https://doi.org/10.1016/j.intimp.2019.105967 Received 10 September 2019; Received in revised form 30 September 2019; Accepted 7 October 2019 1567-5769/ © 2019 Elsevier B.V. All rights reserved.
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Fig. 1. Structure of Edaravone (3-methyl-1-phenyl2-pyrazolin-5-one, formerly MC-186). The drug is sold under diﬀerent brand names including Radicut® and Radicava® (Mitsubishi Tanabe Pharma Corporation, Japan), Nuravon™ (Abbott), Univone and Arone and others. The keto-enol tautomerism and resonance of EDA as well as the equilibrium between the neutral and anionic forms of EDA are represented. Adapted from .
OH N H 3C
N H 3C
↘ DNA damages ↘ Lipid peroxidation ↘ Protein oxidation ↘ Mitochondrial dysfunction ↘ Oxidative stress, ↘ Cytokines production…
Fig. 2. Illustration of the mechanism of action of EDA which provides a cerebral neuroprotection by reducing oxidative stress and inﬂammation. The scavenging of reactive oxygen species (ROS) by EDA reduces the extent of DNA damages, oxidation of lipids and proteins, thus diminishing the cellular oxidative stress. The drug induces a reduction of the production of cytokines (such as IL6, IL-10, IL-18, TNF-α, IL-1β) leading to the antiinﬂammatory response. These eﬀects limit the neuronal dysfunctions.
underline. EDA treatment was found to decrease a range of pro-inﬂammatory cytokines/chemokines (such as IL-1β, IL-6, IL-10, TNF-α) in various pharmacological models and in Human [14–16]. Thus, EDA has multiple biological eﬀects acting as an oxygen radical scavenger, a modulator of NFκB and Nrf2 activities, and an inhibitor of chemokines production, limiting the development and progression of inﬂammatory cascades which are implicated in various disease processes. Because these oxidative and inﬂammatory processes are implicated in cancer as well, I have examined the potential interest of EDA in cancer therapy, either as a direct anticancer agent alone or in combination, or as an indirect support to alleviate the adverse side eﬀects of various anticancer treatments. As discussed here, EDA presents little interest as an anticancer agent per se but could be much more useful as a protector, to reduce the side eﬀects of cancer radio-, chemo- and immuno-therapies.
In addition to scavenging free radicals, EDA targets diﬀerent intracellular signaling pathways suppressing the release of proinﬂammatory cytokines and the activation of inﬂammatory cells. In fact, EDA displays both anti-oxidative and anti-inﬂammatory eﬀects (Fig. 2). Recently, novel key elements to clarify the mechanism of action of EDA have been published. The drug prevents the transfer of the transcription factor protein NFκB from the cytoplasm to the nucleus, whilst promoting the expression of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor) known to regulate the expression of antioxidant genes (Fig. 3). The suppression of NFκB-mediated inﬂammatory activation and promotion of Nrf2 antioxidant pathway are two key processes that mediate EDA activities . In recent years, NRF2 signaling has emerged as the central pathway that protects cells from variety of stressors; it plays a major role in inﬂammation . The expression of NRF2 downstream genes maintain the oxidative homeostasis and cell survival. EDA was found to activate the Nrf2/ARE signaling pathway under diﬀerent conditions, and this eﬀect apparently underlies its protective eﬀects against the oxidative damage associated with the disease considered, stroke, or Alzheimer’s or other oxidative stress-associated pathologies [11–13]. The capacity of EDA to reduce systemic inﬂammatory responses under oxidative stress is important to
2. Limited anticancer activities of edaravone and derivatives EDA alone displays modest antiproliferative eﬀects against tumor cells. The drug was found to dose-dependently limit tumor growth of some cancer cell lines in vitro (e.g. MCF-7 breast cancer cells) but the eﬀect was very limited, essentially observed at high concentrations 2
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pyrazolone derivative TELIN which inhibits human telomerase. This compound binds to the telomerase enzyme, not to the quadruplex DNA target, to function as an enzyme blocker . But no cellular information was reported with this compound. In fact, only two studies refer directly to the design and synthesis of antitumor EDA analogues. The ﬁrst, in 2011, described the synthesis and structure–activity relationships for a series of 4-aminomethylidene derivatives of EDA and compound 3q was found to elicit a noticeable antiproliferative activity against certain cancer cells . For example, this compound proved to be about 10-times more potent that EDA against the breast cancer cell line MDA-MB-453, with an IC50 of about 10 μM (which is still low compared to conventional cytotoxic drugs) . More recently, another series of anticancer EDA analogues was designed and a few compounds showed a superior antiproliferative activity against cancer cells compared to EDA. One of the best compounds in this series, compound 7c, showed a modest cytotoxic activity in vitro . In the next sections, the potential use of EDA as a cytoprotector against toxicities caused by some chemo-, radio- and immuno-therapeutic drugs is discussed (Fig. 5).
3. Potent protection from chemotherapy-induced toxic eﬀects The cell-protective activity of EDA has been exploited to limit the side eﬀects of certain anticancer drugs. Notably cisplatin, one of the most widely used cytotoxic agents for various solid tumors, induces frequent dose-dependent toxic side eﬀects, in particular oto-, nephro-, gastrointestinal- and neuro-toxicities. These secondary eﬀects reduce the life quality of patients and may require dosage adjustments weakening the treatment eﬀect. EDA was tested as an antioxidant to alleviate cisplatin-induced neurobehavioral deﬁcits in rats. An in vivo treatment with EDA was found to up-regulate Nrf2/HO-1 gene expression and to prevent cisplatin-induced NFκB activation. These biochemical changes led to a reduction of the neurobehavioral and cognitive deﬁcits observed in rats treated with cisplatin . Two studies reported that EDA can protect against cisplatin-induced ototoxicity by preventing apoptosis and limiting ROS production in cells and in a zebraﬁsh model [28,29]. Other studies have shown that EDA may be potentially useful to prevent acute renal failure induced by cisplatin. The treatment with EDA attenuated the renal dysfunction and renal tubular damages in rats cotreated with cisplatin (i.p.) and EDA (i.v.) [30–32]. EDA limits druginduced DNA damages in renal proximal tubules. Moreover, a recent study showed that EDA ameliorated also cisplatin-induced renal injury in the chronic phase in rats, with a reduction of proximal tubule injury, interstitial ﬁbrosis and mononuclear cell inﬁltration . Collectively, these studies provide a rational to investigate further the protective eﬀects of EDA in cancer patients treated with cisplatin. Very recently, the use of EDA to overcome the neurotoxicity of the anticancer drug cyclophosphamide was proposed. High-dose cyclophosphamide - used to treat metastatic breast cancer, certain lymphoma or leukemia - can lead to severe nephrotoxicity and neurotoxicity. In rats, the co-administration of EDA was found to ameliorate the behavioral and histopathological changes induced by cyclophosphamide . The cardiotoxicity of anthracycline cytotoxic drugs is a major issue, frequently limiting the eﬃcacy of the cancer treatment. Patients receiving doxorubicin or daunorubicin are at risk of cardiomyopathy and cardio-protection measures are often needed. EDA was found to prevent doxorubicin-induced cardiac deterioration in vivo and apparently does not aﬀect daunorubicin’s anticancer eﬀect . Interestingly in a toxicity study performed in dogs, EDA was found to alleviate the cardiac abnormalities produced by doxorubicin. Pretreatment with EDA improved the biochemical, electrocardiographic and physiological parameters characteristic of the anticancer drug-induced cardiac injury .
Fig. 3. EDA improves the antioxidant defense via an upregulation of Nrf2 expression and inhibition of the pro-inﬂammatory factor NFκB. EDA modulates the crosstalk between the two transcription factors. EDA-induced Nrf2 activation (via Keap1…) promotes the expression of antioxidant proteins, while NFκB inhibition (via p50/p65…) reduces the expression of pro-inﬂammatory proteins. Nrf2 antagonizes NFκB activation through proteasomal activation. The complementary action on the Nrf2/NFκB pathway leads to a reduction of oxidative stress and inﬂammation by EDA.
(100–300 μM) and without eﬀect on cell viability . By itself, EDA is a weak cytotoxic agent but it can react with another compound to generate a more potent cytotoxic product. A case was described with a pterin derivative, DFP that is used to produce singlet oxygen (1O2) under UV-A radiation, for anti-cancer photodynamic therapy. EDA was found to form a cell-permeable, cytotoxic ROS-generating adduct DFP-E [18,19]. Certain anticancer drugs have the capacity to activate the transcription factor NFκB which is one mechanism of tumor resistance and survival. This is the case of irinotecan (CPT-11), a conventional cytotoxic drug targeting topoisomerase I, largely used to treat solid tumors, in particular colon cancers . The blockade of NFκB activation can shift the death/survival balance toward apoptosis. EDA has been shown to inhibit activation of NFκB-induced by SN38, the active metabolite of CPT-11 and thereby to enhance apoptosis and its antitumor eﬀects both in vitro and in vivo. The combination of EDA and CPT-11 reduced colon26 tumor growth in mice and decreased the number of pulmonary metastases, much more eﬀectively than CPT-11 alone . The capacity of EDA to inhibit activation of NFκB and to suppress oxidative stress and endoplasmic reticulum stress (EDA is known to decrease the induction of the stress marker GRP78) should also confer to EDA a capacity to protect against CPT–11–induced intestinal mucosa injury. As such, EDA could improve the anticancer activity and decrease the intestinal side eﬀects of CPT-11. Numerous anticancer pyrazole derivatives have been designed and synthesized over the past ten years but there are not many pyrazolone derivatives of EDA. A few innovative compounds are indicated in Fig. 4. Recently, the phenyl-pyrazolone derivative DPDHN was found to reduce tumor cell proliferation, with a modest eﬃcacy . In another series of pyrazolones, compound 9 proved to be active in vitro and in vivo at reducing tumor growth in a dose-dependent manner. Notably, this compound inhibited the subcutaneous growth of multidrug resistant KBv200 cells in mice. It required complexation with Cu to exert its antiproliferative activity . Another interesting compound is the 3
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Fig. 4. Chemical structures of selected pyrazolone derivatives structurally related to EDA which have shown antiproliferative activities: DPDHN , TELIN , compounds 3q , 7c  and 9 .
of EDA for the treatment of radionecrosis . Radiation therapy can induce also major toxicities, in particular oral mucositis which is frequent in patients treated with radiotherapy for a head and neck cancer. Here again, the antioxidant eﬀects of EDA can be useful to limit tissue damages. The oral mucositis score was reduced in a murine model of mucositis induced on the tongue tips of mice receiving a single high dose of X-rays in the presence of EDA versus no treatment . Moreover, cancer chemo- and radio-therapy can cause salivary gland atrophy, resulting in low salivary secretion in cancer patients, which can potentially exacerbate oral ulcerative mucositis. EDA has been shown to suppress parotid acinar cells dysfunctions in primary culture, suggesting a beneﬁc role in the prevention of salivary gland dysfunction . 5. Edaravone and immuno-therapy of cancer Another remarkable pharmacological property of EDA can be underlined here: its recently demonstrated capacity to ameliorate autoimmune thyroiditis. EDA was found to dose-dependently mitigate thyroiditis severity in an experimental rat model through the involvement of ROS and HO-1 dependent STAT3/PI3K/Akt pathway . In this study, EDA signiﬁcantly increased mRNA levels of IL-10, IL-4, TNFα and IFN-β, while inhibiting mRNA level of IL-17. This discovery opens interesting clinical perspective because autoimmune thyroid diseases (such as Graves’ disease and Hashimoto thyroiditis) can arise after PD-1/PD-L1 blocking therapies in cancer patients. Therapy with immune checkpoint inhibitors, and in particular anti-PD-1-antibodies (e.g. pembrolizumab and nivolumab), are frequently associated with (sometime irreversible) thyroid dysfunctions including thyroiditis [49,50]. Hashimoto thyroiditis is associated with IL-17A secretion, leading to T cell activation . Chronic inﬂammation surrounding tumor upregulates PD-L1 expression on tumor cells by the release of cytokines, which act to inhibit tumor destruction . Therefore, it would be particularly interesting to investigate the potential eﬀect of EDA to limit the incidence of autoimmune thyroiditis upon anti-PD-1 therapy. Based on the experimental data , one can anticipate that in cancer patients receiving a PD-1-targeted immune checkpoint inhibitor, EDA can decrease the incidence of autoimmune thyroiditis by decreasing the number of IL-17-positive T cells.
Fig. 5. EDA and cancer therapy. The drug can protect non-tumor cells from the oxidative damages and inﬂammation induced by chemo and radiotherapy of cancer. It could also help to alleviate the unwanted eﬀects of immuno-therapy, such as autoimmune thyroiditis induced by anti-PD-1 antibodies, via its antiinﬂammatory action.
4. Management of radiotherapy-induced side eﬀects EDA displays signiﬁcant radioprotective eﬀects. It can protect neurons of the hippocampus from cell death after irradiation . In vitro at high concentrations (3 mg/ml), the drug was found to suppress apoptosis induced by X-ray in human T-cell leukemia MOLT4 cells, by inhibiting p53 and caspases . EDA signiﬁcantly inhibits γH2AX foci formation in MOLT-4 cells after irradiation  and reduces DNA damage in γ-irradiated lymphocytes . But at low concentrations (0.75 mg/ml), EDA enhanced X-ray-induced apoptosis of cell lines harboring p53 wild-type status, such as MOLT-4, Nalm-6, and HepG2 . The radioprotection eﬀect has been observed also in vivo after ip administration of EDA to mice, the drug increased the lethal dose of radiation . Interestingly, EDA can protect neural stem cells (NSC), but not brain tumor cells, from cell death after irradiation. It was found to restore the diﬀerentiation and self-renewal ability of NSC after irradiation, whereas the less sensitive brain tumor cells were not aﬀected . Thus, EDA could be useful to preserve neurogenesis after radiation therapy and to limit radiation-induced brain injury. In a population of 154 patients with nasopharyngeal carcinoma, a noticeable improvement in neurologic symptoms was observed in the majority (61%) of patients treated with EDA . This ﬁrst clinical study suggested that EDA may be useful to reduce radiation-induced brain necrosis but, as pointed out recently, further evidence is needed to support the utility
6. Discussion EDA was developed ﬁrst for the treatment of acute brain infarction and, a few years later, for the treatment of ALS. Today, the drug is currently investigated in a number of neurologic and non-neurologic pathologies . As discussed here, EDA may be useful to improve speciﬁc cancer treatments. There are common genetic and metabolic characteristics between ALS and cancer (oxidative unbalance, 4
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damages. By potently scavenging free radicals, EDA can reduce the progression of diseases associated with an oxidative burst, such as ALS, and protect diﬀerent organ from damages . The cytoprotective effects of EDA can be exploited to prevent from myocardial, retinal, lung, intestinal, liver, pancreatic and renal injuries . It is therefore logical to note the potential interest of EDA in cancer, which is also frequently associated with an oxidative stress. The antiproliferative eﬀects of EDA are relatively modest, alone or in combination with other drugs, and of limited interest. This is not surprising for a drug primarily endowed with cell protective eﬀects. However, there may be an interest to combine EDA with irinotecan to combat metastases to the central nervous system, which are associated with considerable mortality in patients with cancer. In sharp contrast, the capacity of EDA to protect from damages induced by oxygen radicals is much more pertinent in oncology. Many chemo and radio-therapeutic anticancer treatments involve reactive oxygen/nitrogen species to block the cancer cell metabolism (DNA damages, lipid peroxidation, mitochondrial perturbations). EDA can be useful to limit the damages induced by cytotoxic drugs in non-tumoral tissues, notably to lessen the nephrotoxic or ototoxic eﬀects of cisplatin, to reduce the cardiotoxicity of anthracyclines or to diminish the side eﬀects of radiotherapy, as described above. Similar protective eﬀects have been evoked with other scavengers of ROS. For example, the hydroxyl radical scavenger dimethylthiourea has been shown to prevent the renal damage caused by cisplatin . Another antioxidant, protocatechuic acid (3,4-dihydroxybenzoic acid) which is abundant in green tea, protects against nephrotoxicity induced by doxorubicin . Other compounds could be cited but the advantage of EDA is that it is a drug with a proven safety after 18 years of use in Human as a modulator of free radical scavenging pathways in brain-related diseases. As a drug already authorized for use in Humans, its applications could be more easily extended to cancer-related conditions. Another major advantage of EDA is its capacity to cross the blood–brain barrier, to diﬀuse into the central nervous system and to act on the cerebral vasculature and neuronal networks, oﬀering a potent neuroprotection. Therefore, the drug is well adapted to combat the neurotoxicity of cisplatin and cyclophosphamide, as described above but possibly also the neurotoxic eﬀects of other established anticancer drugs like the taxanes (e.g. paclitaxel) and vinca-alkaloids (e.g. vincristine). EDA is a remarkable anti-oxidative and anti-inﬂammatory drug. It functions as a NFκB inhibitor and Nrf2 activator, like for examples the cytoprotective and anticancer phytochemicals resveratrol, curcumin, epigallocathechin-3-gallate and sulforaphane [81,82]. The polyphenol honokiol, the main active ingredient from the bark of Magnolia oﬃcinalis, also exhibits anticancer and neuroprotective activities [83,84]. It functions as a potent ROS scavenger and promotes nuclear translocation and activation of Nrf2 and displays potent neuroprotection against oxidative stress-mediated cell damage . Its mode of action resembles that of EDA. The potential interest of EDA to mitigate autoimmune thyroiditis is very interesting in the context of cancer therapy with immune checkpoint inhibitors. Therapeutic antibodies targeting the PD-1/PD-L1 pathway have revolutionized the treatment of speciﬁc cancers, notably non-small cell lung cancer and melanoma, but they also induce lifethreatening toxicities. Autoimmune thyroiditis induced by antibodies that block the interaction between PD-1 and PD-L1 is frequently observed in cancer patients . It can lead sometimes to irreversible thyroid dysfunctions. Interleukin (IL)-17 (a hallmark cytokine of Thelper 17 cells) plays a signiﬁcant role in the pathogenesis of autoimmune thyroid diseases, in particular Hashimoto’s thyroiditis  and EDA has the capacity to inhibit expression of IL-17 implicated in the destruction of thyrocytes . The use of EDA in the therapy of autoimmune thyroiditis induced by anti-PD-1/PD-L1 antibodies could be important. It is interesting to note that the anti-inﬂammatory and antimalarial natural product dihydroartemisinin (DHA) has also been found to attenuates autoimmune thyroiditis . For both EDA and DHA, the
Fig. 6. Illustration of the interconnexion between cancer and ALS, with common genetic drivers or targets implicated in the pathologies (the small green and red squares illustrate common or distinct genes and targets). The two drugs approved for the treatment of ALS could be useful to improve cancer treatment (riluzole) or to limit the side eﬀects of cancer therapies (edaravone). Conversely, the anticancer drugs 5-ﬂuorouracil (5-FU, antimetabolite) and masitinib (kinases inhibitor) have shown activities in experimental models of ALS. (For interpretation of the references to color in this ﬁgure legend, the reader is referred to the web version of this article.)
inﬂammation processes). Epidemiological studies have suggested that ALS relates to cancer [53–55]. For example, the human mouse mammary tumor virus like-2 (HML-2) is activated in several tumors and has been related to prostate cancer progression and motor neuron diseases, including ALS . Therefore, common therapeutic strategies may be developed (Fig. 6). Riluzole, the only other drug approved for the treatment of ALS, is also largely studied for its anticancer eﬀects, notably for the treatment of brain tumors, prostate cancer and melanoma with a phase 2 trial ongoing [57–59]. Riluzole can block proliferation and/or sensitize cancer cells to radiation [60,61]. The drug functions as a glutamate release inhibitor (GRM1 antagonist), but its anticancer activity is apparently independent of GRM1 . In parallel, a clinical trial is assessing the beneﬁt of riluzole in the prevention of oxaliplatininduced peripheral neuropathy . At the same time, it is interesting to note that an inverse repurposing strategy, from cancer to ALS, is conducted with the tyrosine kinase masitinib (approved for mast cell tumors in dogs) to control neuroinﬂammation in ALS [64,65]. Certain anticancer microtubule stabilizing drugs (e.g., paclitaxel) can be repositioned for brain disorders including ALS [66,67]. Recently, the well-established antimetabolite 5-ﬂuorouracil, used to treat many types of cancers, was found to be active in a mice model of ALS . The natural products berberine and celastrol have shown activities in experimental models of both cancer and ALS [69–71]. The anti-inﬂammatory drug methylprednisolone also shows eﬀects in both cancer and ALS . The antileukemic drug imatinib has been considered for the treatment of ALS . There are common epidemiological, genetic, and histopathological links between cancer and ALS . The repositioning of an anti-ALS drug like EDA in oncology, and vice-versa, is really conceivable (Fig. 6). A parallel can be established also with the mechanism of action of the triterpenoid drug omaveloxolone (RTA 408) which potently activates Nrf2 with subsequent antioxidant functions. This semisynthetic compound activates Nrf2, reduces NFκB phosphorylation and nuclear translocation, attenuates (ozone-induced) ROS release, decreases proinﬂammatory cytokine production and reduces the percentage of IL17+ γδT cells [74,75]. It is currently assessed in Human both for its antitumor activity and the management of brain diseases [76,77]. The two drugs EDA and omaveloxolone are structurally totally distinct but they share a similar mechanism of action that supports their potential interest both in cancer and brain diseases. EDA is a low-molecular weight free radical scavenger that targets oxidative stress, a process largely implicated in neuronal and vascular 5
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STAT3/PI3K/Akt pathway was found to be implicated in the process. The use of EDA to prevent from or to alleviate cancer immunotherapyinduced autoimmune thyroiditis no doubt merits further studies. The therapeutic impact can be very signiﬁcant. Collectively, the information reviewed here clearly suggest that EDA can play a role to support cancer treatments. One of the limitations of EDA is its very low aqueous solubility (and solubilization in vehicle and intestinal ﬂuids) which is the primary determining factor for its intestinal absorption . This limitation imposes a parenteral administration of the drug, whereas oral administration would be preferable for the use in chronic diseases and cancer. Novel oral and sublingual tablet formulations of EDA are investigated currently to improve its oral bioavailability. The results look promising [90–93]. Formulations to facilitate the brain delivery are also investigated . They could be useful for the treatment of brain tumors or metastases. A future for EDA in cancer can be envisaged.
Declaration of Competing Interest The author declares no conﬂict of interest.
 Z.K. Ali, D.E. Baker, Formulary drug review: edaravone, Hosp. Pharm. 52 (2017) 732–736.  R.P. Dash, R.J. Babu, N.R. Srinivas, Two decades-long journey from riluzole to edaravone: revisiting the clinical pharmacokinetics of the only two amyotrophic lateral sclerosis therapeutics, Clin. Pharmacokinet. 57 (2018) 1385–1398.  Q. Jin, Y. Cai, S. Li, H. Liu, X. Zhou, C. Lu, X. Gao, J. Qian, J. Zhang, S. Ju, C. Li, Edaravone-encapsulated agonistic micelles rescue ischemic brain tissue by tuning blood-brain barrier permeability, Theranostics 7 (2017) 884–898.  K. Watanabe, M. Tanaka, S. Yuki, M. Hirai, Y. Yamamoto, How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J. Clin. Biochem. Nutr. 62 (2018) 20–38.  K. Akaiwa, K. Namekata, Y. Azuchi, X. Guo, A. Kimura, C. Harada, Y. Mitamura, T. Harada, Edaravone suppresses retinal ganglion cell death in a mouse model of normal tension glaucoma, Cell Death Dis. 8 (2017) e2934.  E. Toyota, Y. Miyamoto, K. Imai, Y. Neishi, T. Kawamoto, H. Okura, K. Yoshida, Development of cardiac dysfunction induced by repetitive transient myocardial ischemia is inhibited by edaravone in conscious rats, Clin. Exp. Pharmacol. Physiol. 36 (2009) e20–25.  W.W. Zhang, F. Bai, J. Wang, R.H. Zheng, L.W. Yang, E.A. James, Z.Q. Zhao, Edaravone inhibits pressure overload-induced cardiac ﬁbrosis and dysfunction by reducing expression of angiotensin II AT1 receptor, Drug Des. Devel. Ther. 1 (2017) 3019–3033.  K. Kikuchi, N. Takeshige, N. Miura, Y. Morimoto, T. Ito, S. Tancharoen, K. Miyata, C. Kikuchi, N. Iida, H. Uchikado, N. Miyagi, N. Shiomi, T. Kuramoto, I. Maruyama, M. Morioka, K.I. Kawahara, Beyond free radical scavenging: beneﬁcial eﬀects of edaravone (Radicut) in various diseases (Review), Exp. The.r Med. 3 (2012) 3–8.  M. Zhang, C.H. Teng, F.F. Wu, L.Y. Ge, J. Xiao, H.Y. Zhang, D.Q. Chen, Edaravone attenuates traumatic brain injury through anti-inﬂammatory and anti-oxidative modulation, Exp. Ther. Med. 18 (2019) 467–474.  W. Tu, H. Wang, S. Li, Q. Liu, H. Sha, The anti-inﬂammatory and anti-oxidant mechanisms of the Keap1/Nrf2/ARE signaling pathway in chronic diseases, Aging Dis. 10 (2019) 637–651.  Y.P. Xu, F. Han, J. Tan, Edaravone protects the retina against ischemia/reperfusion–induced oxidative injury through the PI3K/Akt/Nrf2 pathway, Mol. Med. Rep. 16 (2017) 9210–9216.  D. Zhang, Y. Xiao, P. Lv, Z. Teng, Y. Dong, Q. Qi, Z. Liu, Edaravone attenuates oxidative stress induced by chronic cerebral hypoperfusion injury: role of ERK/ Nrf2/HO-1 signaling pathway, Neurol. Res. 40 (2018) 1–10.  L. Zhang, Y. Guo, H. Wang, L. Zhao, Z. Ma, T. Li, J. Liu, M. Sun, Y. Jian, L. Yao, Y. Du, G. Zhang, Edaravone reduces Aβ-induced oxidative damage in SH-SY5Y cells by activating the Nrf2/ARE signaling pathway, Life Sci. 221 (2019) 259–266.  N. Fujiwara, A.T. Som, L.D. Pham, B.J. Lee, E.T. Mandeville, E.H. Lo, K. Arai, A free radical scavenger edaravone suppresses systemic inﬂammatory responses in a rat transient focal ischemia model, Neurosci. Lett. 633 (2016) 7–13.  Z. Liu, C. Yang, X. Meng, Z. Li, C. Lv, P. Cao, Neuroprotection of edaravone on the hippocampus of kainate-induced epilepsy rats through Nrf2/HO-1 pathway, Neurochem. Int. 112 (2018) 159–165.  R. Yi, Y. Zhizhou, S. Zhaorui, Z. Wei, C. Xin, N. Shinan, Retrospective study of clinical features and prognosis of edaravone in the treatment of paraquat poisoning, Medicine (Baltimore) 98 (2019) e15441.  R. Suzuki, R.K. Gopalrao, H. Maeda, P. Rao, M. Yamamoto, Y. Xing, S. Mizobuchi, S. Sasaguri, MCI-186 inhibits tumor growth through suppression of EGFR phosphorylation and cell cycle arrest, Anticancer Res. 25 (2005) 1131–1138.  T. Arai, M. Nonogawa, K. Makino, N. Endo, H. Mori, T. Miyoshi, K. Yamashita, M. Sasada, M. Kakuyama, K. Fukuda, The radical scavenger edaravone (3-methyl-1phenyl-2-pyrazolin-5-one) reacts with a pterin derivative and produces a cytotoxic
substance that induces intracellular reactive oxygen species generation and cell death, J. Pharmacol. Exp. Ther. 324 (2008) 529–538. M. Nonogawa, T. Arai, N. Endo, S.P. Pack, T. Kodaki, K. Makino, Reactive oxygen species generation through NADH oxidation by pterin derivatives, Nucleic Acids Symp. Ser. (Oxf.) (2008) 567–568. C. Bailly, Irinotecan: 25 years of cancer treatment, Pharmacol. Res. 148 (2019) 104398. S. Kokura, N. Yoshida, N. Sakamoto, T. Ishikawa, T. Takagi, H. Higashihara, N. Nakabe, O. Handa, Y. Naito, T. Yoshikawa, The radical scavenger edaravone enhances the anti-tumor eﬀects of CPT-11 in murine colon cancer by increasing apoptosis via inhibition of NF-kappaB, Cancer Lett. 229 (2005) 223–233. K.P.R. Rani, Y.S. Mary, A. Fernandez, A.P. S, Y.S. Mary, R. Thomas, Single crystal XRD, DFT investigations and molecular docking study of 2- ((1,5-dimethyl-3-oxo-2phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino)naphthalene-1,4-dione as a potential anti-cancer lead molecule, Comput. Biol. Chem. 78 (2019) 153–164. X.H. Wang, X.K. Wang, Y.J. Liang, Z. Shi, J.Y. Zhang, L.M. Chen, L.W. Fu, A cellbased screen for anticancer activity of 13 pyrazolone derivatives, Chin. J. Cancer 29 (2010) 980–987. Y. Kakiuchi, N. Sasaki, M. Satoh-Masuoka, H. Murofushi, K. Murakami-Murofushi, A novel pyrazolone, 4,4-dichloro-1-(2,4-dichlorophenyl)-3-methyl-5-pyrazolone, as a potent catalytic inhibitor of human telomerase, Biochem. Biophys. Res. Commun. 320 (2004) 1351–1358. V. Marković, S. Erić, Z.D. Juranić, T. Stanojković, L. Joksović, B. Ranković, M. Kosanić, M.D. Joksović, Synthesis, antitumor activity and QSAR studies of some 4-aminomethylidene derivatives of edaravone, Bioorg. Chem. 39 (2011) 18–27. N. Polkam, V.R. Ramaswamy, P. Rayam, T.R. Allaka, H.S. Anantaraju, S. Dharmarajan, Y. Perumal, D. Gandamalla, N.R. Yellu, S. Balasubramanian, J.S. Anireddy, Synthesis, molecular properties prediction and anticancer, antioxidant evaluation of new edaravone derivatives, Bioorg. Med. Chem. Lett. 26 (2016) 2562–2568. A. Jangra, M. Kwatra, T. Singh, R. Pant, P. Kushwah, S. Ahmed, D. Dwivedi, B. Saroha, M. Lahkar, Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inﬂammatory mediators in the rat hippocampus, Eur. J. Pharmacol. 791 (2016) 51–761. G.J. Im, J. Chang, S. Lee, J. Choi, H.H. Jung, H.M. Lee, S.H. Ryu, S.K. Park, J.H. Kim, H.J. Kim, Protective role of edaravone against cisplatin-induced ototoxicity in an auditory cell line, Hear. Res. 330 (2015) 113–118. S.J. Hong, G.J. Im, J. Chang, S.W. Chae, S.H. Lee, S.Y. Kwon, H.H. Jung, A.Y. Chung, H.C. Park, J. Choi, Protective eﬀects of edaravone against cisplatininduced hair cell damage in zebraﬁsh, Int. J. Pediatr. Otorhinolaryngol. 77 (2013) 1025–1031. K. Sueishi, K. Mishima, K. Makino, Y. Itoh, K. Tsuruya, H. Hirakata, R. Oishi, Protection by a radical scavenger edaravone against cisplatin-induced nephrotoxicity in rats, Eur. J. Pharmacol. 451 (2002) 203–208. M. Satoh, N. Kashihara, S. Fujimoto, H. Horike, T. Tokura, T. Namikoshi, T. Sasaki, H. Makino, A novel free radical scavenger, edarabone, protects against cisplatininduced acute renal damage in vitro and in vivo, J. Pharmacol. Exp. Ther. 305 (2003) 1183–1190. T. Iguchi, M. Nishikawa, B. Chang, O. Muroya, E.F. Sato, T. Nakatani, M. Inoue, Edaravone inhibits acute renal injury and cyst formation in cisplatin-treated rat kidney, Free Radic Res. 38 (2004) 333–341. N. Koike, A. Sasaki, T. Murakami, K. Suzuki, Eﬀect of edaravone against cisplatininduced chronic renal injury, Drug Chem. Toxicol. 1–10 (2019). S. Singh, A. Kumar, Protective eﬀect of edaravone on cyclophoshamide induced oxidative stress and neurotoxicity in rats, Curr. Drug Saf. (2019) in press. [Epub ahead of print]. E. Ikegami, R. Fukazawa, M. Kanbe, M. Watanabe, M. Abe, M. Watanabe, M. Kamisago, M. Hajikano, Y. Katsube, S. Ogawa, Edaravone, a potent free radical scavenger, prevents anthracycline-induced myocardial cell death, Circ. J. 71 (2007) 1815–1820. Y. Xin, S. Zhang, L. Gu, S. Liu, H. Gao, Z. You, G. Zhou, L. Wen, J. Yu, Y. Xuan, Electrocardiographic and biochemical evidence for the cardioprotective eﬀect of antioxidants in acute doxorubicin-induced cardiotoxicity in the beagle dogs, Biol. Pharm. Bull. 34 (2011) 1523–1526. K. Motomura, M. Ogura, A. Natsume, H. Yokoyama, T. Wakabayashi, A free-radical scavenger protects the neural progenitor cells in the dentate subgranular zone of the hippocampus from cell death after X-irradiation, Neurosci. Lett. 485 (2010) 65–70. N. Sasano, A. Enomoto, Y. Hosoi, Y. Katsumura, Y. Matsumoto, K. Shiraishi, K. Miyagawa, H. Igaki, K. Nakagawa, Free radical scavenger edaravone suppresses x-ray-induced apoptosis through p53 inhibition in MOLT-4 cells, J Radiat Res. 48 (2007) 495–503. Z. Hong, Y. Kase, T. Moritake, A. Gerelchuluun, L. Sun, K. Suzuki, T. Terunuma, K. Yasuoka, H. Kumada, K. Anzai, H. Sakurai, T. Sakae, K. Tsuboi, Lineal energybased evaluation of oxidative DNA damage induced by proton beams and X-rays, Int. J. Radiat Biol. 89 (2013) 36–43. L. Chen, Y. Liu, L. Dong, X. Chu, Edaravone protects human peripheral blood lymphocytes from γ-irradiation-induced apoptosis and DNA damage, Cell Stress Chaperones. 20 (2015) 289–295. N. Sasano, A. Enomoto, Y. Hosoi, Y. Katsumura, Y. Matsumoto, A. Morita, K. Shiraishi, K. Miyagawa, H. Igaki, K. Nakagawa, Edaravone, a known free radical scavenger, enhances X-ray-induced apoptosis at low concentrations, Cancer Lett. 293 (2010) 52–57. K. Anzai, M. Furuse, A. Yoshida, A. Matsuyama, T. Moritake, K. Tsuboi, N. Ikota, In vivo radioprotection of mice by 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone; Radicut), a clinical drug, J. Radiat. Res. 45 (2004) 319–323. J. Ishii, A. Natsume, T. Wakabayashi, H. Takeuchi, H. Hasegawa, S.U. Kim,
International Immunopharmacology 77 (2019) 105967
  
brain disorders, Front. Cell. Neurosci. 12 (2018) 226.  A. Rando, M. de la Torre, A. Martinez-Muriana, P. Zaragoza, A. Musaro, S. Hernández, X. Navarro, J.M. Toivonen, R. Osta, Chemotherapeutic agent 5ﬂuorouracil increases survival of SOD1 mouse model of ALS, PLoS ONE 14 (2019) e0210752.  B.J. Traynor, L. Bruijn, R. Conwit, F. Beal, G. O'Neill, S.C. Fagan, M.E. Cudkowicz, Neuroprotective agents for clinical trials in ALS: a systematic assessment, Neurology 67 (2006) 20–27.  C.F. Chang, Y.C. Lee, K.H. Lee, H.C. Lin, C.L. Chen, C.J. Shen, C.C. Huang, Therapeutic eﬀect of berberine on TDP-43-related pathogenesis in FTLD and ALS, J. Biomed. Sci. 23 (2016) 72.  Y.H. Li, S.B. Liu, H.Y. Zhang, F.H. Zhou, Y.X. Liu, Q. Lu, L. Yang, Antioxidant eﬀects of celastrol against hydrogen peroxide-induced oxidative stress in the cell model of amyotrophic lateral sclerosis, Sheng Li Xue Bao 69 (2017) 751–758.  M.C. Evans, P.J. Gaillard, M. de Boer, C. Appeldoorn, R. Dorland, N.R. Sibson, M.R. Turner, D.C. Anthony, H.B. Stolp, CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis, Acta Neuropathol. Commun. 2 (2014) 66.  T. Lukas, T. Siddique, Cancer drug repurposing for treating amyotrophic lateral sclerosis (ALS) (S5.004), Neurology 92 (2019) S5.004.  C.C. Yang, C.C. Lin, M.J. Jou, L.D. Hsiao, C.M. Yang, RTA 408 inhibits interleukin1β-induced MMP-9 expression via suppressing protein kinase-dependent NF-κB and AP-1 activation in rat brain astrocytes, Int. J. Mol. Sci. 20 (2019) E2826.  J.H. Zhang, X. Yang, Y.P. Chen, J.F. Zhang, C.Q. Li, Nrf2 Activator RTA-408 protects against ozone-induced acute asthma exacerbation by suppressing ROS and γδT17 cells, Inﬂammation. 42 (2019) 1843–1856.  B.C. Creelan, D.I. Gabrilovich, J.E. Gray, C.C. Williams, T. Tanvetyanon, E.B. Haura, J.S. Weber, G.T. Gibney, J. Markowitz, J.W. Proksch, S.A. Reisman, M.D. McKee, M.P. Chin, C.J. Meyer, S.J. Antonia, Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a ﬁrst-inhuman trial of patients with advanced solid tumors, Onco Targets Ther. 10 (2017) 4239–4250.  D.R. Lynch, J. Farmer, L. Hauser, I.A. Blair, Q.Q. Wang, C. Mesaros, N. Snyder, S. Boesch, M. Chin, M.B. Delatycki, P. Giunti, A. Goldsberry, C. Hoyle, M.G. McBride, W. Nachbauer, M. O'Grady, S. Perlman, S.H. Subramony, G.R. Wilmot, T. Zesiewicz, C. Meyer, Safety, pharmacodynamics, and potential beneﬁt of omaveloxolone in Friedreich ataxia, Ann. Clin. Transl. Neurol. 6 (2018) 15–26.  K. Kikuchi, K.I. Kawahara, H. Uchikado, N. Miyagi, T. Kuramoto, T. Miyagi, Y. Morimoto, T. Ito, S. Tancharoen, N. Miura, K. Takenouchi, Y. Oyama, B. Shrestha, F. Matsuda, Y. Yoshida, S. Arimura, K. Mera, K.I. Tada, N. Yoshinaga, R. Maenosono, Y. Ohno, T. Hashiguchi, I. Maruyama, M. Shigemori, Potential of edaravone for neuroprotection in neurologic diseases that do not involve cerebral infarction, Exp. Ther. Med. 2 (2011) 771–775.  N.A. Santos, C.S. Bezerra, N.M. Martins, C. Curti, M.L. Bianchi, A.C. Santos, Hydroxyl radical scavenger ameliorates cisplatin-induced nephrotoxicity by preventing oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria, Cancer Chemother. Pharmacol. 61 (2008) 145–155.  O.R. Molehin, A.A. Adeyanju, S.A. Adefegha, A.O. Oyeyemi, K.A. Idowu, Protective mechanisms of protocatechuic acid against doxorubicin-induced nephrotoxicity in rat model, J. Basic Clin. Physiol. Pharmacol. 30 (2019) 4.  M. Sova, L. Saso, Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review, Drug Des. Devel. Ther. 12 (2018) 3181–3197.  F. Sivandzade, S. Prasad, A. Bhalerao, L. Cucullo, NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches, Redox Biol. 21 (2019) 101059.  C. Rajagopal, M.B. Lankadasari, J.M. Aranjani, K.B. Harikumar, Targeting oncogenic transcription factors by polyphenols: a novel approach for cancer therapy, Pharmacol. Res. 130 (2018) 273–291.  K. Banik, A.M. Ranaware, V. Deshpande, S.P. Nalawade, G. Padmavathi, D. Bordoloi, B.L. Sailo, M.K. Shanmugam, L. Fan, F. Arfuso, G. Sethi, A.B. Kunnumakkara, Honokiol for cancer therapeutics: a traditional medicine that can modulate multiple oncogenic targets, Pharmacol. Res. 144 (2019) 192–209.  Y. Hou, S. Peng, X. Li, J. Yao, J. Xu, J. Fang, Honokiol alleviates oxidative stressinduced neurotoxicity via activation of Nrf2, ACS Chem. Neurosci. 9 (2018) 3108–3116.  D. Álvarez-Sierra, A. Marín-Sánchez, P. Ruiz-Blázquez, Gil C de Jesús, C. IglesiasFelip, Ó. González, A. Casteras, R.F. Costa, P. Nuciforo, R. Colobran, R. PujolBorrell, Analysis of the PD-1/PD-L1 axis in human autoimmune thyroid disease: Insights into pathogenesis and clues to immunotherapy associated thyroid autoimmunity, J. Autoimmun. 102285 (2019).  T. Zake, S. Skuja, I. Kalere, I. Konrade, V. Groma, Upregulated tissue expression of T helper (Th) 17 pathogenic interleukin (IL)-23 and IL-1β in Hashimoto's thyroiditis but not in Graves' disease, Endocr. J. 66 (2019) 423–430.  H. Liu, Q. Tian, X. Ai, Y. Qin, Z. Cui, M. Li, J. Yang, D. Zhai, Y. Liu, S. Chen, J. Meng, T. Sun, H. Zhou, C. Yang, Dihydroartemisinin attenuates autoimmune thyroiditis by inhibiting the CXCR3/PI3K/AKT/NF-κB signaling pathway, Oncotarget. 8 (2017) 115028–115040.  S. Hyung, Y.S. Jeong, J. Yeo, Y.K. Song, M.S. Kim, Y.J. Im, H.J. Maeng, S.J. Chung, Identiﬁcation of the primary determining factor(s) governing the oral absorption of edaravone in rats, Eur. J. Pharm. Sci. 123 (2018) 312–320.  A. Parikh, K. Kathawala, J. Li, C. Chen, Z. Shan, X. Cao, Y.J. Wang, S. Garg, X.F. Zhou, Self-nanomicellizing solid dispersion of edaravone: part II: in vivo assessment of eﬃcacy against behavior deﬁcits and safety in Alzheimer's disease model, Drug Des. Devel. Ther. 12 (2018) 2111–2128.
J. Yoshida, The free-radical scavenger edaravone restores the diﬀerentiation of human neural precursor cells after radiation-induced oxidative stress, Neurosci. Lett. 423 (2007) 225–230. Y. Tang, X. Rong, W. Hu, G. Li, X. Yang, J. Yang, P. Xu, J. Luo, Eﬀect of edaravone on radiation-induced brain necrosis in patients with nasopharyngeal carcinoma after radiotherapy: a randomized controlled trial, J. Neurooncol. 120 (2014) 441–447. C. Chung, A. Bryant, P.D. Brown, Interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery, Cochrane Database Syst. Rev. 7 (2018) CD011492. N. Nakajima, S. Watanabe, T. Kiyoi, A. Tanaka, K. Suemaru, H. Araki, Evaluation of edaravone against radiation-induced oral mucositis in mice, J. Pharmacol. Sci. 127 (2015) 339–343. H. Sakurai, M. Yokoyama, O. Katsumata-Kato, J. Fujita-Yoshigaki, Suppression of parotid acinar cell dysfunction by the free radical scavenger 3-methyl-1-phenyl-2pyrazolin-5-one, J. Oral Sci. 61 (2019) 475–480. H. Li, J. Min, X. Mao, X. Wang, Y. Yang, Y. Chen, Edaravone ameliorates experimental autoimmune thyroiditis in rats through HO-1-dependent STAT3/PI3K/Akt pathway, Am. J. Transl. Res. 10 (2018) 2037–2046. S.M. Ferrari, P. Fallahi, F. Galetta, E. Citi, S. Benvenga, A. Antonelli, Thyroid disorders induced by checkpoint inhibitors, Rev. Endocr. Metab. Disord. 19 (2018) 325–333. J.L. Mengíbar, I. Capel, T. Bonﬁll, I. Mazarico, L.C. Espuña, A. Caixàs, M. Rigla, Simultaneous onset of type 1 diabetes mellitus and silent thyroiditis under durvalumab treatment, Endocrinol. Diabetes Metab. Case Rep. 2019 (2019) 1. L.T. Han, J.Q. Hu, B. Ma, D. Wen, T.T. Zhang, Z.W. Lu, W.J. Wei, Y.L. Wang, Y. Wang, T. Liao, Q.H. Ji, IL-17A increases MHC class I expression and promotes T cell activation in papillary thyroid cancer patients with coexistent Hashimoto's thyroiditis, Diagn. Pathol. 14 (2019) 52. B.A. Imblum, Z.W. Baloch, D. Fraker, V.A. LiVolsi, Pembrolizumab-induced thyroiditis, Endocr Pathol. 30 (2019) 163–167. D.M. Freedman, R.E. Curtis, S.E. Daugherty, J.J. Goedert, R.W. Kuncl, M.A. Tucker, The association between cancer and amyotrophic lateral sclerosis, Cancer Causes Control 2 (2013) 55–60. M. Yamaguchi, Y. Azuma, H. Yoshida, ALS and cancer, J. Carciong. Mutagen 7 (2016) 6. I. Yamamoto, Y. Azuma, M. Yamaguchi, Cancer-related genes and ALS, Front Biosci. (Landmark Ed). 24 (2019) 1241–1258. G. Ibba, C. Piu, E. Uleri, C. Serra, A. Dolei, Disruption by SaCas9 endonuclease of HERV-Kenv, a retroviral gene with oncogenic and neuropathogenic potential, inhibits molecules involved in cancer and amyotrophic lateral sclerosis, Viruses 10 (2018) E412. S. Sperling, T. Aung, S. Martin, V. Rohde, M. Ninkovic, Riluzole: a potential therapeutic intervention in human brain tumor stem-like cells, Oncotarget. 8 (2017) 96697–96709. J.M. Mehnert, A.W. Silk, J.H. Lee, L. Dudek, B.S. Jeong, J. Li, J.M. Schenkel, E. Sadimin, M. Kane, H. Lin, W.J. Shih, A. Zloza, S. Chen, J.S. Goydos, A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma, Pigment Cell Melanoma Res. 31 (2018) 534–540. K.M. Wadosky, M. Shourideh, D.W. Goodrich, S. Koochekpour, Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen-dependent and castration-resistant prostate cancer cells, Prostate 79 (2019) 140–150. M.K. Lemieszek, A. Stepulak, K. Sawa-Wejksza, A. Czerwonka, C. Ikonomidou, W. Rzeski, Riluzole inhibits proliferation, migration and cell cycle progression and induces apoptosis in tumor cells of various origins, Anticancer Agents Med. Chem. 18 (2018) 565–572. A.J. Khan, S. LaCava, M. Mehta, D. Schiﬀ, A. Thandoni, S. Jhawar, S. Danish, B.G. Haﬀty, S. Chen, The glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo, Oncotarget. 10 (2019) 2824–2834. C.L. Speyer, M.A. Nassar, A.H. Hachem, M.A. Bukhsh, W.S. Jafry, R.M. Khansa, D.H. Gorski, Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1, Breast Cancer Res. Treat. 157 (2016) 217–228. N. Kerckhove, J. Busserolles, T. Stanbury, B. Pereira, V. Plence, F. Bonnetain, I. Krakowski, A. Eschalier, D. Pezet, D. Balayssac, Eﬀectiveness assessment of riluzole in the prevention of oxaliplatin-induced peripheral neuropathy: RILUZOX01: protocol of a randomised, parallel, controlled, double-blind and multicentre study by the UNICANCER-AFSOS Supportive Care intergroup, BMJ Open. 9 (2019) e027770. E. Trias, P.H. King, Y. Si, Y. Kwon, V. Varela, S. Ibarburu, M. Kovacs, I.C. Moura, J.S. Beckman, O. Hermine, L. Barbeito, Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS, JCI Insight. 3 (2018) 123249. J.S. Mora, A. Genge, A. Chio, C.J. Estol, D. Chaverri, M. Hernández, S. MarÍn, J. Mascias, G.E. Rodriguez, M. Povedano, A. Paipa, R. Dominguez, J. Gamez, M. Salvado, C. Lunetta, C. Ballario, N. Riva, J. Mandrioli, A. Moussy, J.P. Kinet, C. Auclair, P. Dubreuil, V. Arnold, C.D. Mansﬁeld, O. HermineAB10015 STUDY GROUP, Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial, Amyotroph Lateral Scler Frontotemporal Degener. (2019) 1–10, https://doi.org/10.1080/21678421.2019. 1632346 Epub ahead of print. K.R. Brunden, J.Q. Trojanowski, A.B. Smith 3rd, V.M. Lee, C. Ballatore, Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease, Bioorg. Med. Chem. 22 (2014) 5040–5049. A. Varidaki, Y. Hong, E.T. Coﬀey, Repositioning microtubule stabilizing drugs for
International Immunopharmacology 77 (2019) 105967
in healthy male volunteers, Clin. Ther. 40 (2018) 1683–1691.  Q. Li, W. Huang, J. Yang, J. Wang, M. Hu, J. Mo, Y. Cheng, Z. Ou, Z.J. Zhang, S. Guan, Gastric retention pellets of edaravone with enhanced oral bioavailability: absorption mechanism, development, and in vitro/in vivo evaluation, Eur. J. Pharm. Sci. 119 (2018) 62–69.
 A. Parikh, K. Kathawala, C.C. Tan, S. Garg, X.F. Zhou, Self-nanomicellizing solid dispersion of edaravone: part I - oral bioavailability improvement, Drug Des. Devel. Ther. 12 (2018) 2051–2069.  J. Wang, X. Chen, B. Yuan, W. Wang, C. Xu, W. Zhao, P. Zhao, Y. Wang, X. Zhao, Y. Wang, Bioavailability of edaravone sublingual tablet versus intravenous infusion